Studies of the clinical pharmacology of anticancer and antiretroviral drugs used in the treatment of children with cancer and HIV-infection focus on the development of new agents and the pharmacokinetics and pharmacodynamics of standard drugs (e.g., anthracyclines, vinca alkaloids, antimetabolites, platinum analogs, dideoxynucleosides). An emphasis is placed on studying the CNS pharmacology of new and standard drugs and on the development of new treatment approaches for CNS tumors. An integrated approach incorporating preclinical studies in in vitro and animal models, as well as clinical trials and clinical pharmacokinetic studies, is utilized. For new systemic anticancer drugs, analytical techniques to assay drug concentrations are developed and preclinical pharmacokinetic studies are performed in a nonhuman primate model which is highly predictive of drug disposition in humans. Cytotoxicity studies in pediatric tumor cell lines are used to define cytotoxic concentrations, schedule dependence, and the potential spectrum of activity of the new agent against pediatric tumors. These preclinical studies guide in the design of the initial phase I and II trials and pharmacokinetic studies in children with refractory cancer. New agents studied by the PET Section in children include topotecan, all-trans-retinoic acid, pyrazoloacridine, docetaxel, intravenous thioguanine, tomudex, paclitaxel, 9-cis-retinoic acid, RMP-7, and carboxypeptidase-G2 (CPDG2). We have shown that CPDG2 is a highly effective new rescue agent for patients receiving high-dose methotrexate who develop renal dysfunction. Systemically administered drugs that penetrate well across the blood-brain barrier are identified, and targeted for studies in patients with brain tumors (topotecan, temozolomide). We have also developed several new agents (diaziquone, mercaptopurine, mafosfamide, topotecan) that can be administered intrathecally for the treatment of meningeal relapse. The section is also collaborating with other DCS branches and has performed pharmacokinetic studies in adults treated with both investigational and standard agents (e.g., retinoids and fluorouracil). The studies of existing agents are designed to identify more rational approaches to their use by developing limited sampling strategies to simplify drug monitoring and defining pharmacodynamic correlates that relate drug concentrations to toxicity or efficacy of the drug. The approach to the study of antiretroviral drugs in children parallels that of the anticancer drugs. Drug assays are developed, preclinical pharmacokinetic studies are performed in the animal model with an emphasis on defining the CNS pharmacology of the agent, and clinical pharmacokinetic/pharmacodynamic studies are performed in children treated on Pediatric Branch trials of new and existing antiretroviral drugs. We have also developed a rapid fluorescence-based assay for HIV-1 integrase that should prove to be useful for screening for inhibitors of this critical step of the HIV life cycle. The novel fluorescent probes (U.S. Patent #5,525,711, issued 6/11/96) developed for this assay are nucleoside analogs that can be substituted for guanosine in DNA oligonucleotides and may prove useful in the study of a other protein/DNA interactions. HIV/AIDS-related work accounted for 30% of this project.